The skin is the largest organ of the mammalian body and serves several critical functions. In some cases, the skin is disrupted by trauma (e.g. laceration, abrasion, burns or puncture) or by ulceration (e.g. diabetic foot ulcers). Disruptions in the skin which do not heal, or spontaneously recur, are known as chronic wounds (Fowler (1990) in Chronic wounds: an overview. In: Krasner D, editor. Chronic wound care: a clinical source book for healthcare professionals. King of Prussia, Pa.: Health Management Publications, Inc.; pp. 12-8 and Singh et al. (2004) Asian J Surg 27:326-32).
Approximately 1% to 2% of individuals will be affected by leg ulceration during their lifetime, and this figure will likely increase as the population ages (Rees and Hirshberg (1999). Adv Wound Care 1999; 12:4-7 and Callam M. (1992) Phlebology 7:S6-S12). Global wound care expenses reaches up to $13 to $15 billion annually (Walmsley (2002) In: Clinical reports. London: PJB Publications, Ltd.).
Patient groups suffering chronic wounds include, but are no limited to, diabetic patients, geriatric patients and patients with circulatory problems. Also, chronic wounds can appear as a result of acute trauma or as a post surgery symptom.
Chronic wounds may vary in size, depth and stage of healing. Wounds can contain necrotic tissue, infection, scabs, or exudates (purulent, cerotic).
Chronic wounds can be classified by their cause such as pressure, diabetic, ischemic, venous, and tear and/or by the nature of the wound itself such as its depth and/or stage of healing and/or discharge and/or infections. Burns are another wound type which is difficult to treat.
Conventional burn treatment typically relies upon a topical antibiotic cream (e.g. Silver sulfadiazine) followed by a non-stick dressing and gauze. Use of biologic dressings based upon cultured cell grafts and/or fractionated blood products has also been suggested. According to different burn management strategies, frequency of dressing changes can vary from twice per day to about once per week.
A number of non conventional burn treatment strategies have been proposed. A non-exhaustive overview of some of the art follows.
WO/2001/021195 describes a dressing including preformed fibrin that functions as a non-adhesive covering of a burned skin surface as well as functioning as a delivery vehicle for pharmaceutical compounds that are entrapped within the fibrin clot.
J. Travis (Science News Online 155 (25); Jun. 19, 1999) describes fibrin bandages produced by Martin MacPhee at the American Red Cross' Holland Laboratory in Rockville, Md. The bandages employ a cloth made of biodegradable material saturated with thrombin, fibrinogen, and factor 13 purified from human blood. The bandages are brittle until they get wet, and then they become flexible.
US 2002/0146446 describes a surgical-medical dressing which uses a sandwich of two extracellular matrices grown on a composite composed of gelatin-fibronectin-heparan sulfate. The culture medium used to grow the two cell types (dermal fibroblasts and dermal microvascular endothelial cells forming the second extracellular matrix) is the conditioned medium (CM) obtained from human umbilical endothelial cells used to form the first extracellular matrix. All cells in tissue culture are detached leaving their secreted acellular matrix behind and intact. This CM can also neutralize the enzyme DISPASE commercially used to detach cultured epithelial sheets (“Cultured epithelial autografts” (CEAs)) from the matrix on which the human epidermal cells, forming the sheets are grown. CEAs are clinically used in wound and burn management
Henderson L. et al, discloses the healing of superficial skin burns by a autologous platelet gel dressing. (Ear, Nose & Throat Journal, 2003).
U.S. Pat. No. 3,723,244 describers a method of producing fibrin in sheet form by centrifuging an aqueous dispersion of fibrin wherein monomeric fibrin molecules are combined by polymerization to form strands of fibrin. The centrifuging step is conducted in a vessel having a wall for interception of particles undergoing centrifugal acceleration therein and at a speed pelletizing on said wall the strands of fibrin resulting from polymerization, so that the pelletized strands interlock to form a sheet which is recovered from the wall. The aqueous dispersion can be blood plasma and the resultant fibrin sheets are described as useful as a dressing for burns.
U.S. Pat. No. 6,521,265 describes a method of promoting healing of a bleeding wound including mixing a substantially anhydrous compound of a salt ferrate, which hydrates in the presence of water to produce Fe+++ and oxygen, combined with an insoluble cation exchange material, with a quantity of an aqueous media such as whole blood taken directly from the wound with deionized water; aqueous sodium chloride; aqueous dissolved gelatin; aqueous carboxy methacel; and aqueous carbohydrate solution to form a spreadable paste. The paste is applied to the wound within a short working time to promote blood clotting. According to the description, the presence of oxygen, substantially reduces the level of bacteria, virus and fungus at the wound as a protective coating forms over the wound.
U.S. Pat. No. 4,347,841 describes biological dressing for burn wounds formed by removing free hemoglobin from a red blood cell concentrate which is subjected to hemolysis. The dressing contains the stroma, subcellular elements and precipitated protein from the human red blood corpuscle concentrate freed from the hemoglobin and can be used in a pulverulant or layer form with, if desired, an appropriate support.
US 2007/0275461 and US 2004/0171145 describe artificial dermis obtained from plasma with platelets and human fibroblasts. The plasma with platelets is obtained from fractionating whole blood from the patient by light centrifugation, and the human fibroblasts are obtained from a skin biopsy. Clotting is obtained by adding calcium. The artificial dermis is described as providing for rapid growth of keratinocytes seeded on its surface to build an artificial skin which can easily be transplanted. Large areas of artificial dermis are described as being obtained from a small skin biopsy and minimal quantities of plasma with platelets. The artificial skin is described as useful to treat major burns, chronic skin ulcers, or be used with genetically altered cells as a vehicle for gene therapy.
US 2004/0124564 describes a process for the preparation of a chemically modified fibrin-fibrillar protein (FFP) composite sheet for medical application and the FFP composite prepared thereby. According to the description, the FFP sheet finds potential use as a dressing aid in the treatment of various external wounds including burn wounds.
Use of purified or fractionated blood components in other medical contexts is also described. A non-exhaustive overview of some of the art follows.
Khalafi et al. (Eur J Cardiothorac Surg 2008; 34:360-364.) describes application of platelet rich and platelet poor plasma to significantly reduce occurrences of chest wound infection, chest drainage, and leg wound drainage in coronary artery bypass grafts.
Medtronic, Inc., Minneapolis, MV; USA produces devices for processing autologous blood to concentrate platelet-rich plasma into an autologous platelet gel for use in surgery for improving tissue healing.
Some commercially available wound care products use blood fractions and/or factors isolated from blood.
For example, a variety of growth factors have been found to play a role in the wound healing process, including platelet derived growth factor (PDGF), epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factor. Various wound healing technologies based on fractionated blood or blood derived growth factors are commercially available.
One commercially available technology employs recombinant DNA techniques to create purified growth factors. REGANEX™ Gel (manufactured by Systagenix Wound Management) is a topical gel, containing the active ingredient becaplermin with an activity similar to that of human platelet derived growth factor (PDGF). This recombinant growth factor is produced by recombinant DNA technology by insertion of the gene for the B chain of platelet-derived growth factor (PDGF) into Saccharomyces cerevisiae.
Another commercially available technology employs platelet rich plasma (PRP). PRP is isolated from whole blood by centrifugation. Autologous PRP contains a mixture of activated growth factors cytokines and chemokines, with reduced potential for immune response. Exposure of PRP to a solution of thrombin and calcium chloride results in the polymerization of fibrin from fibrinogen, creating a platelet gel which can then be applied to wounds. The PRP provides the wound with growth factors, chemokines and cytokines that promote angiogenesis and regulate cell growth and formation of new tissue. AutoloGel™ (manufactured by Cytomedix, Inc.) and SafeBlood® (manufactured by SafeBlood Technologies) are two autologous blood-derived products that can be prepared at the bedside for immediate application. Both AutoloGel™ and SafeBlood® have been specifically marketed for wound healing.
Another commercially available technology employs fibrin glues or sealants with hemostasis and gluing properties which enhance wound healing. Commercial fibrin glues are created from pooled homologous human donors. TISSEEL™ (manufactured by Baxter) is an example of commercially available fibrin sealant. The action of this product allegedly simulates key features of the physiological process of wound closure. The product contains a highly concentrated fibrinogen aprotinin solution, which among other ingredients contains Factor XIII, and a solution of thrombin and calcium chloride are applied to the wound area, where the mixture coagulates. The presence of Factor XIII causes the fibrin to crosslink, which gives the coagulum additional resilience.